The present invention relates to novel heterocyclic aromatic oxazole compounds. More particularly, the present invention relates to heterocyclic aromatic oxazole compounds having antipyretic activity, analgesic activity, anti-inflammatory activity, and in particular, selective inhibitory activity against cyclooxygenase-2 (COX-2), pharmaceutically acceptable salts thereof, intermediates for producing them and pharmaceuticals useful as anti-inflammatory agents causing less side-effects such as disorders in the digestive tract, which comprise these heterocyclic aromatic oxazole compounds.
It has been conventionally known that arachidonic acid metabolites, prostaglandin E2 (PGE2), prostaglandin I2 (PGI2) and thromboxane B2 (TXB2) are deeply involved in inflammations. An important enzyme in this arachidonic acid metabolism is cyclooxygenase. Cyclooxygenase is a synthase which produces prostaglandin H2 (PGH2) from arachidonic acid via prostaglandin G2 (PGG2), and includes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).
With respect to COX-1, cDNA cloning was performed in 1988 and its primary structure and induction by various factors have been clarified [Yokoyama, C. et al.: Biochem. Biophys. Res. Commun., 165: 888-894 (1989); Smith, W. L. et al.: Biochim. Biophys. Acta, 1083: 1-17 (1991); DeWitt, D. L.: Biochim. Biophys. Acta, 1083: 121-134 (1991)]. On the other hand, the existence of an isozyme of COX-1, namely, COX-2, was suggested in 1989 [Holtzman, M. J. et al.: J. Biol. Chem., 267: 21438-21445 (1992)], and cDNAs of COX-2 of chicken, mouse and human have been cloned since 1991 [Xie, W. et al.: Proc. Natl. Acad. Sci. USA, 88: 2692-2696 (1991); Kujubu, D. A. et al.: J. Biol. Chem., 266: 12866-12872 (1991); Hla, T. et al.: Pror. Natl. Acad. Sci. USA, 89: 7384-7388 (1992)]. COX-2 is quickly induced by phorbol ester, lipopolysacharide (LPS) and the like, and the relationship with inflammation and bronchial asthma has been inferred.
COX-1 systemically and constantly exists in almost all cells and is physiologically concerned with the generation of prostaglandin (PG) necessary for the functions of, for example, stomach and kidney. Therefore, when COX-1 is inhibited, the biosynthesis of PG by vasodilative PGE2 and PGI2, which protect gastric mucosa, is suppressed, and the protective action on the gastric mucosa becomes degraded, as a result of which ulcer is caused. With regard to a symptom associated with a decrease in renal blood flow, in general terms, the renal blood flow can be increased by promoting the production of vasodilative PGE2 in the body, thereby to appropriately maintain glomerular filtration rate. However, if the production of such vasodilative PG is suppressed due to the inhibition of COX-1, the renal blood flow becomes less, so that a side-effect such as the onset of ischemic acute renal insufficiency is sometimes caused.
On the other hand, COX-2 exists in particular sites such as monocytes, synovial cells, granulosa cells and intravenous endothelial cells, and is topically expressed when inflammation is caused. It is therefore considered that PG generated by COX-2 is deeply concerned with inflammation and tissue disorders.
Currently, non-steroidal anti-inflammatory drugs (NSAID) such as aspirin, mefenamic acid, diclofenac, indomethacin, ibuprofen and naproxen have been widely used in clinical situations. Most of these NSAIDs are anti-inflammatory drugs which selectively inhibit cyclooxygenase (COX) and are associated with side-effects such as disorders in the digestive tract. Such side-effects are considered to be caused by the fact that they, though certainly selectively inhibit COX, inhibit both COX-1 and COX-2.
It follows therefrom that selective inhibition, without inhibition of COX-1, of solely COX-2 which is specifically induced at the inflammatory sites, would enable provision of a superior anti-inflammatory drug free of side-effects such as disorders in the digestive tract (e.g., ulcer).
There are various reports on anti-inflammatory drugs having selective COX-2 inhibitory activity, which aim at reducing side-effects such as disorders in the digestive tract.
For example, W094/15932 discloses, as COX-2 inhibitors, 5-membered heterocyclic compounds substituted by bisaryl, such as thiophene, furan and pyrrole, which are specifically exemplified by 3-(4-methylsulfonylphenyl)-4-(4-fluorophenyl)thiophene. However, this publication merely shows a 5-membered heterocyclic compound such as thiophene having aryl or heteroaryl at the 3-position or 4-position.
Moreover, various reports deal with anti-inflammatory drugs having cyclooxygenase-inhibitory action, prostaglandin synthesis-inhibitory action or thromboxane A2 synthesis-inhibitory action.
For example, Japanese Patent Unexamined Publication No. 141261/1991 discloses pyrazole derivatives such as ethyl 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3carboxylate; Japanese Patent Unexamined Publication No. 183767/1982 discloses thiazole derivatives such as 2-methylthio-5-phenyl-4-(3-pyridyl)-thiazole; and Japanese Patent Unexamined Publication No. 58981/1985 discloses thiazole derivatives such as 2-ethyl-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole. These publications mention that they are useful as anti-inflammatory drugs, whereas they do not disclose if they have selective inhibitory action on COX-2 to reduce side-effects, or any suggestion of it.
There are other reports on the following heterocyclic aromatic compounds.
For example, U.S. Pat. No. 4,632,930 discloses oxazole compounds such as 5-cyclohexyl-4-(4-methylsulfonylphenyl)-xcex1,xcex1-bis(trifluoromethyl)oxazole-2-methanol. Yet, the compounds disclosed therein are effective for hypertension and their use as anti-inflammatory drugs or any suggestion to that effect are not included.
Japanese Patent Application under PCT laid-open under Kohyo No. 500054/1984 discloses oxazole derivatives having heteroaryl or carbon ring aryl at the 4-position or 5-position of oxazole ring and having carboxy, ester or amidized carboxy via lower alkylene at the 2-position thereof, such as ethyl 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-propionate; and Japanese Patent Application under PCT laid-open under Kohyo No. 500055/1984 discloses imidazole derivatives having heteroaryl and/or carbon ring aryl at the 4-position or 5-position of imidazole ring and having formyl or acetalized formyl via lower alkylene at the 2-position thereof, such as 2-[4-phenyl-5-(3-pyridyl)-imidazol-2-yl]-acetaldehyde dimethyl acetal. These publications teach that these compounds are effective as dermal antiphlogistic or mucosal antiphlogistic for inflammatory dermal diseases, but do not teach or even suggest that they have selective inhibitory action on COX-2.
Japanese Patent Unexamined Publication No. 70446/1993 discloses N-thiazolylsulfonamide derivatives such as N-[5-cyclohexyl-4-(4-methoxyphenyl)thiazol-2-yl]trifluoromethanesulfonamide; and Japanese Patent Unexamined Publication No. 83372/1990 discloses cyclohexylimidazole derivatives such as 4-cyclohexyl-5-phenyl-2-t-butyl-imidazole. These publications only exemplify cyclohexyl as a substituent and include no suggestion as to the substitution with phenyl substituted by aminosulfonyl, lower alkylaminosulfonyl or lower alkylsulfonyl.
WO94/27980 discloses oxazole compounds such as 2-phenyl-4-cyclohexyl-5-(4-methylsulfonylphenyl)oxazole as COX-2 inhibitors. However, the compounds described in this publication are mainly characterized by 4-fluorophenyl and 4-methylsulfonylphenyl at the 4-position and 5-position of oxazole ring, and do not suggest the compounds having specific substituents in combination, as in the present invention.
Not only in COX-2 inhibitors but also in the field of anti-inflammatory drugs, preferable phenyl substituent for 5membered heterocyclic ring skeleton has been conventionally considered to be monosubstituted phenyl such as 4-methylsulfonylphenyl and 4-methoxyphenyl, and di-substituted phenyl has been barely tried (e.g., UK Patent No. 1206403).
The present inventors have intensively studied with the aim of providing a novel compound having antipyretic activity, analgesic activity and anti-inflammatory activity, which is free of side-effects such as disorders in the digestive tract. Surprisingly, they have found that a compound having a secondary substituent such as halogen atom, in particular, fluorine atom, introduced into phenyl such as 4-lower allylsulfonylphenyl, 4-aminosulfonylphenyl or 4-lower alkylaminosulfonylphenyl, as a substituent for oxazole, has superior selective inhibitory action on COX-2, which resulted in the completion of the present invention.
That is, the present invention relates to heterocyclic aromatic oxazole compounds as shown in the following (1) to (21), pharmaceutically acceptable salts thereof, intermediate compounds for producing such compounds and pharmaceutical compositions comprising such heterocyclic aromatic oxazole compound.
(1) Heterocyclic aromatic oxazole compounds of the formula (I) 
wherein
Z is an oxygen atom;
one of R and R1 is a group of the formula 
wherein R3 is lower alkyl, amino or lower alkylamino, and R4, R5, R6 and R7 are the same or different and each is hydrogen atom, halogen atom, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or amino, provided that at least one of R4, R5, R6 and R7 is not hydrogen atom, and the other is optionally substituted cycloalkyl; optionally substituted heterocyclic group or optionally substituted aryl; and
R2 is a lower alkyl or a halogenated lower alkyl, and pharmaceutically acceptable salts thereof.
(2) Heterocyclic aromatic oxazole compounds of the above (1), wherein R1 is a group of the formula 
wherein R3xe2x80x2 is lower alkyl or amino, at least one of R4xe2x80x2, R5xe2x80x2, R6xe2x80x2 and R7xe2x80x2 is halogen atom or lower alkyl and the rest is hydrogen atom or halogen atom, and pharmaceutically acceptable salts thereof.
(3) Heterocyclic aromatic oxazole compounds of the above (1), wherein R1 is a group of the formula 
wherein R3xe2x80x3 is methyl or amino, R5xe2x80x3 is fluorine atom and R6xe2x80x3 is hydrogen atom or fluorine atom, and R2 is methyl, and pharmaceutically acceptable salts thereof.
(4) Heterocyclic aromatic oxazole compounds of the above (1), wherein R1 is a group of the formula 
wherein R31xe2x80x3, R5xe2x80x3 and R6xe2x80x3 are as defined in the above (3); R is optionally substituted cycloalkyl having 5 to 7 carbon atoms, optionally substituted thienyl, optionally substituted furyl, optionally substituted pyrrolyl, optionally substituted morpholino, optionally substituted piperazinyl, optionally substituted piperidyl, optionally substituted phenyl, optionally substituted naphthyl or optionally substituted biphenyl, and R2 is methyl, and pharmaceutically acceptable salts thereof.
(5) Heterocyclic aromatic oxazole compounds of the above (4), wherein R3xe2x80x3 is amino, and pharmaceutically acceptable salts thereof.
(6) Heterocyclic aromatic oxazole compounds of the above (4), wherein R is optionally substituted cycloalkyl having 5 to 7 carbon atoms, optionally substituted phenyl or optionally substituted thienyl, and pharmaceutically acceptable salts thereof.
(7) Heterocyclic aromatic oxazole compounds of the above (4), wherein R is cyclohexyl or 4-fluorophenyl, and R1 is 4-aminosulfonyl-3-fluorophenyl, 4-aminosulfonyl-3,5-difluorophenyl, 3-fluoro-4-methylsulfonylphenyl or 3,5-difluoro-4-methylsulfonylphenyl, and pharmaceutically acceptable salts thereof.
(8) Heterocyclic aromatic oxazole compounds of the above (1), which are selected from the group of:
4-cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyloxazole,
5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole,
5-(4-aminosulfonyl-3,5-difluorophenyl)-4-cyclohexyl-2-methyloxazole,
4-cyclohexyl-5-(3,5-difluoro-4-methylsulfonylphenyl)-2-methyloxazole, and
5-(4-aminosulfonyl-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyloxazole, and pharmaceutically acceptable salts thereof.
(9) Oxime compounds of the following formula (XIxe2x80x2) 
wherein R1xe2x80x3 is 
wherein R4, R5, R6 and R7 are as defined in the above (1), and R1xe2x80x3 is optionally substituted cycloalkyl or optionally substituted aryl.
(10) Oxime compounds of the above (9) wherein R1xe2x80x3 is 3-fluorophenyl or 3,5-difluorophenyl, and Rxe2x80x3 is cyclohexyl or 4-fluorophenyl.
(11) Ketone compounds of the following formula (IVxe2x80x3) 
wherein R1xe2x80x3 and Rxe2x80x3 are respectively as defined in the above (9).
(12) Ketone compounds of the above (11) wherein R1xe2x80x3 is 3-fluorophenyl or 3,5-difluorophenyl, and Rxe2x80x3 is cyclohexyl or 4-fluorophenyl.
(13) Ketomethylene compounds of the following formula (IVxe2x80x2xe2x80x3) 
wherein Rxe2x80x2xe2x80x3 is optionally substituted cycloalkyl having 5 to 7 carbon atoms, optionally substituted phenyl or optionally substituted thienyl, and R1xe2x80x2xe2x80x3 is a group of the formula 
wherein R3xe2x80x2, R4xe2x80x2, R5xe2x80x2, R6xe2x80x2 and R7xe2x80x2 are as defined in the above (2).
(14) Ketomethylene compounds of the above (13) wherein Rxe2x80x2xe2x80x3 is cyclohexyl, and R1xe2x80x2xe2x80x3 is 4-aminosulfonyl-3-fluorophenyl, 4-aminosulfonyl-3,5-difluorophenyl, 3-fluoro-4-methylsulfonylphenyl or 3,5-difluoro-4-methylsulfonylphenyl.
(15) Ester compounds of the following formula (V) 
wherein R, R1, R2 and Z are as defined in the above (1).
(16) Ester compounds of the above (15) wherein R is cycloalkyl and R2 is lower alkyl.
(17) Amide compounds of the following formula (XVIIIxe2x80x2) 
wherein R1xe2x80x3 and Rxe2x80x3 are respectively as defined in the above (9), and Z and R2 are as defined in the above (1).
(18) Amide compounds of the above (17) wherein R1xe2x80x3 is 3-fluorophenyl or 3,5-difluorophenyl, Rxe2x80x3 is cyclohexyl or 4-fluorophenyl, and R2 is lower alkyl.
(19) Pharmaceutical compositions comprising a pharmaceutically acceptable carrier, and a heterocyclic aromatic oxazole compound of the above (1) or a pharmaceutically acceptable salt thereof.
(20) Cyclooxygenase-2 inhibitors comprising a pharmaceutically acceptable carrier, and a heterocyclic aromatic oxazole compound of the above (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
(21) Anti-inflammatory agents comprising a pharmaceutically acceptable carrier, and a heterocyclic aromatic oxazole compound of the above (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
As used herein, lower alkyl means an optionally branched alkyl having 1 to 4 carbon atoms, which is exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, with preference given to methyl.
Lower alkylamino is that wherein amino group is substituted by the above-mentioned lower alkyl, and is exemplified by methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino and tert-butylamino. Preferred are methylamino and dimethylamino.
Halogen atom means chlorine atom, bromine atom, fluorine atom and the like, with preference given to chlorine atom and fluorine atom. Particularly preferred is fluorine atom.
Lower alkoxy is an optionally branched alkoxy having 1 to 4 carbon atoms, which is exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, with preference given to methoxy.
Cycloalkyl means a cycloalkyl having 3 to 8 carbon atoms, which is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, with preference given to cycloalkyl having 5 to 7 carbon atoms, such as cyclopentyl, cyclohexyl and cycloheptyl. Particularly preferred is cyclohexyl.
Heterocyclic group is a 5- or 6-membered aromatic heterocyclic ring, saturated heterocyclic ring or condensed heterocyclic ring of these heterocyclic rings and benzene ring, all having, besides carbon atom, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom as atom(s) constituting the ring. Examples thereof include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, morpholino, piperazinyl, piperidyl, pyranyl, thiopyranyl, pyridyl, benzothienyl, benzofuranyl, indole, 4,5,6,7-tetrahydroindole, 4,5,6,7-tetrahydrobenzothienyl and 4,5,6,7-tetrahydrobenzofuranyl, with preference given to thienyl, furyl, pyrrolyl, morpholino, piperazinyl and piperidyl, and particular preference given to thienyl.
Aryl is, for example, phenyl, naphthyl or biphenyl. Preferred is phenyl.
Halogenated lower alkyl is that wherein lower alkyl is substituted by the aboventioned halogen atom, and is exemplified by fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, fluoroethyl, chloroethyl, difluoroethyl, dichloroethyl, trifluoroethyl, trichloroethyl, tetrachloroethyl, pentafluoroethyl and fluoropropoyl, with preference given to fluoromethyl, chloromethyl, dichlpromethyl, difluoromethyl, trichloromethyl and trifluoromethyl.
xe2x80x9cOptionally substitutedxe2x80x9d means that the group may be substituted by 1 to 3 substituents wherein said substituents may be the same or different. The position of the substituents is optional and is not particularly limited. Specific examples include lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl; hydroxy; lower alkoxy such as methoxy, ethoxy, propoxy and butoxy; halogen atom such as fluorine, chlorine and bromine; nitro; cyano; acyl such as formyl, acetyl and propionyl; acyloxy such as formyloxy, acetyloxy and propionyloxy; mercapto; alkylthio such as methylthio, ethylthio, propylthio, butylthio and isobutylthio; amino; alkylamino such as methylamino, ethylamino, propylamino and butylamino; dialkylamino such as dimethylamino, diethylamino, dipropylamino and dibutylamino; carbonyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; amide; trifluoromethyl; alkylsulfonyl such as methylsulfonyl and ethanesulfonyl; aminosulfonyl; cycloalkyl such as cyclopentyl and cyclohexyl; phenyl; and acylamide such as acetamide and propionylamide. Preferred are hydroxy, lower alkyl, lower alkoxy, mercapto, lower alkylthio, halogen atom, trifluoromethyl, alkylcarbonyl, alkoxycarbonyl and acylamide.
More specifically, optionally substituted aryl means an aryl which may be substituted by halogen atom, hydroxy, lower alkyl, lower alkoxy, lower alkylsulfonyl and aminosulfonyl, particularly phenyl, and is exemplified by phenyl, fluorophenyl, methylphenyl, methoxyphenyl, methylsulfonylphenyl and aminosulfonylphenyl, with preference given to phenyl and 4-fluorophenyl.
Optionally substituted heterocyclic group means a heterocyclic group which may be substituted by halogen atom, hydroxy, lower alkyl, lower alkoxy, lower alkylsulfonyl and aminosulfonyl, and particularly means thienyl, furyl, 5-methylthienyl and 5-chlorothienyl. Optionally substituted cycloalkyl means a cycloalkyl which may be substituted by the same substituents as above, with preference given to cyclohexyl.
Examples of preferable R of the heterocyclic aromatic oxazole compounds of the present invention include cyclohexyl, 4-fluorophenyl and 5-chlorothienyl, with particular preference given to cyclohexyl. Preferred as R1 is a group of the formula 
wherein R3, R4, R5, R6 and R7 are as defined above, with particular preference given to a group wherein R3 is amino or methyl, R4 and R7 are hydrogen atoms and at least one of R5 and R6 is fluorine atom. Specific examples include 4-aminosulfonyl-3-fluorophenyl, 3-fluoro-4-methylsulfonylphenyl, 4-aminosulfonyl-3,5-difluorophenyl and 3,5-difluoro-4-methylsulfonylphenyl, with particular preference given to 4-aminosulfonyl-3-fluorophenyl. Preferred as R2 is methyl.
Pharmaceutically acceptable salt may be any as long as it forms a non-toxic salt with the oxazole derivative of the formula (I). Alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, organic base salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt and N,Nxe2x80x2-dibenzylethylenediamine salt, and amino acid salts such as lysine salt and arginine salt are among the examples. It may be a hydrate as the case demands.
The compound of the present invention has particularly superior selective inhibitory action on COX-2 and is expected to make a therapeutic drug useful for antipyresis, pain relief and anti-inflammation, which is free of side-effects such as digestive tract disorders.
When the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof is used as a pharmaceutical preparation, it is generally admixed with pharmacologically acceptable carriers, excipients, diluents, extenders, disintegrators, stabilizers, preservatives, buffers, emulsifying agents, aromatics, colorings, sweeteners, thickeners, flavorings, solubilizers and other additives known per se, such as water, vegetable oil, alcohol such as ethanol and benzyl alcohol, polyethylene glycol, glycerol triacetate gelatin, carbohydrates such as lactose and starch, magnesium stearate, talc, lanolin and petrolatum, and formulated into, by a conventional method, tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules, troches, aerosols, elixirs, suspensions, emulsions, syrups and the like, which can be administered orally or parenterally.
While the dose varies depending on the kind and severity of the disease,, compound to be administered, administration route, and age, sex, body weight etc. of patients, 0.1 mg-1,000 mg, particularly 1 mg-300 mg of compound (I) is generally administered orally to an adult per day.
The compounds of the present invention can be produced, for example, by the following methods. It is needless to say that the method for producing the compounds of the present invention is not limited to these methods. 
wherein R2xe2x80x2 is lower alkyl or halogenated lower alkyl wherein R2xe2x80x2 may be the same with or different from R2, X and Xxe2x80x2 are the same or different and each is halogen atom such as bromine atom and chlorine atom, X1 is halogen atom or hydroxy, X1xe2x80x2 is halogen atom or hydroxy or alkali metal derivative thereof, and R, R1, R2 and Z are as defined above.
Step 1
Compound (IV) can be synthesized by reacting compound (II) with compound (III) in the presence of a metal such as zinc and magnesium in an inert solvent such as 1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, methylene chloride, benzene and toluene at room temperature. In this case, a catalyst such as palladium(O) complex and copper(I) complex may be added.
Step 2
Compound (V) can be synthesized by reacting compound (IV) in acetic acid solvent in the presence of lead tetraacetate, or by refluxing compound (IV) under heating in the presence of a complex such as manganese acetate, in lower alkanecarboxylic acid such as acetic acid and propionic acid corresponding to R2COOH wherein R2 is as defined above and benzoic acid and a solvent such as benzene as necessary.
Step 3
Compound (I) can be synthesized by refluxing compound (V) under heating in the presence of ammonium salt (e.g., lower alkanecarboxylic acid ammonium such as ammonium acetate and ammonium formate), and inorganic ammonium such as ammonium carbonate in an acidic solvent such as lower alkanecarboxylic acid (e.g., formic acid, acetic acid and propionic acid). In this reaction, when R or R1 is aromatic heterocycle, isomers may be produced wherein the 4-position R and the 5-position R1 are reversed.
Compound (I) can be also synthesized by the following route.
Step 4 wherein X1 is hydroxy
This step, Step 6 and Step 7 are advantageous when R2 (e.g., methyl) is converted to other R2 (e.g., R2xe2x80x2 such as ethyl).
When X1 is hydroxy, compound (VI) can be synthesized by reacting compound (V) in the presence of a base such as potassium carbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide in an organic solvent such as methanol, ethanol and dioxane, water or a mixed solvent thereof from under cooling to under heating.
Compound (VI) can be also synthesized by the following Step 5.
Step 5 wherein X1 is halogen atom or hydroxy
Compound (VI) can be synthesized by reacting compound (IV) in the presence of a halogenating agent such as bromine, chlorine and N-bromosuccinimide in an inert solvent such as acetic acid, 1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, methylene chloride, benzene and toluene to give compound (VI) wherein X1 is halogen atom. Compound (VI) wherein X1 is hydroxy can be synthesized by oxidizing compound (IV) with an oxidizing agent such as benzene iodoacetate, or by treating the halogenated compound (VI) obtained above with water in an inert solvent such as acetone, 1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, benzene and toluene.
Step 6
Compound (Vxe2x80x2) can be obtained by reacting compound (VI) and compound (VIIxe2x80x2) by a known method. Specifically, compound (VI) wherein X1 is hydroxy and compound (VIIxe2x80x2) wherein X1xe2x80x2 is halogen atom, or compound (VI) wherein X1 is halogen atom and compound (VIIxe2x80x2) wherein X1xe2x80x2 is hydroxy are reacted in pyridine, or in the presence of a base such as triethylamine and sodium hydroxide, in an organic solvent such as methylene chloride, chloroform and ethanol, from under cooling to under heating. When X1 is halogen atom, alkali metal salt such as sodium acetate may be used instead of carboxylic acid compound (VIIxe2x80x2). In this case, a base may or may not be added.
Step 7
Compound (Ixe2x80x2) can be obtained by treating compound (Vxe2x80x2) in the same manner as in Step 3.
When a compound wherein either R or R1 is 4-aminosulfonyl-3-fluorophenyl is desired, the compound can be produced from a compound having 3-fluoro-4-methylsulfonylphenyl corresponding to the objective compound by a known method.
Instead of obtaining compound (IV) using, as mentioned above, compound (II) or (III) having, as R or R1, 
wherein R3, R4, R5, R6 and R7 are as defined above, compound (IIxe2x80x2) or (IIIxe2x80x2) having 
wherein R4, R5, R6 and R7 are as defined above, may be used as a starting material to give compound (IVxe2x80x2) according to Step 10, which compound is then converted to aminosulfonyl or methylsulfonyl according to the method of Step 15 to give compound (IV). Alternatively, such starting materials (IIxe2x80x2) and (IIIxe2x80x2) may be used to give a non-sulfonylated oxazole compound (XIII) corresponding to the ultimate compound (I) or (Ixe2x80x2) according to Step 1 to Step 7, and the obtained compound (XIII) may be subjected to sulfonylation in the same manner as in Step 15 to give the objective compound (I) or (Ixe2x80x2).
When a compound wherein either R or R1 is phenyl substituted by alkylaminosulfonyl or aminosulfonyl is desired, compound (X) wherein either R8 or R9 is methoxysulfonylphenyl is subjected to the following Step 8 and Step 9 to synthesize compound (IV). 
wherein either R8 or R9 is methoxysulfonylphenyl of the formula 
wherein R4, R5, R6 and R7 are as defined above, and the other is optionally substituted cycloalkyl, optionally substituted heterocyclic group or optionally substituted aryl, and R, R1, X and Xxe2x80x2 are as defined above.
Step 8
Compound (X) can be synthesized in the same manner as in Step 1, using compound (VIII) and compound (IX).
Step 9
When at least one of R and R1 is phenyl having aminosulfonyl or alkylsulfonyl at the 4-position, compound (IV) can be synthesized by heating compound (X) in pyridine, or refluxing compound (X) under heating in the presence of sodium iodide, potassium iodide, lithium iodide and the like, in an organic solvent such as acetone and tetrahydrofuran, after which the obtained compound is reacted with thionyl chloride or oxalyl chloride under heating. Then, the resulting product is aminated or alkylaminated or alkylated by a known method. More specifically, amination or alkylamination is carried out by reacting the resulting product in the presence of aqueous ammonia or alkylamine, or a base such as sodium acetate and ammonium salt such as alkylamine hydrochloride, in an organic solvent such as tetrahydrofuran, ether, toluene, benzene, methylene chloride and dioxane from under cooling to under heating. The alkylation can be carried out by the method described in J. Org. Chem., 56: 4974-4976 (1991).
Compound (I) can be also synthesized by the method of the following Step 10 to Step 15.
This method is directed to finally introducing sulfonyl group in the last Step 15. 
wherein either Rxe2x80x2 or R1xe2x80x2 is phenyl of the formula 
wherein R4, R5, R6 and R7 are as defined above, and the other is a group corresponding to one of R and R1, cycloalkyl which may be substituted by a substituent such as lower alkyl, heterocyclic group such as thienyl and furyl, which may be substituted by a substituent lower alkyl or halogen atom, or aryl which may be substituted by a substituent such as halogen atom, lower alkyl and lower alkoxy, and R, R1, X, Xxe2x80x2 and Z are as defined above.
Step 10
Compound (IVxe2x80x2) can be synthesized in the same manner as in Step 1, wherein compound (IIxe2x80x2) and compound (IIIxe2x80x2) are reacted in the presence of a metal such as zinc and magnesium in an inert solvent such as 1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, methylene chloride, benzene and toluene at room temperature. In this case, a catalyst such as palladium(O) complex and copper(I) iodide complex may be added.
Step 11
Compound (XI) can be synthesized by refluxing under heating compound (IVxe2x80x2) and hydroxylammine hydrochloride in the presence of a base such as sodium acetate, sodium hydroxide and potassium carbonate in an organic solvent such as methanol, ethanol and tetrahydrofuran, water or a mixed solvent thereof.
Step 12
Compound (XII) can be synthesized by reacting compound (XI) in the presence of an acylating agent such as acetic anhydride and acetyl chloride, in pyridine, or in the presence of a base such as triethylamine in an organic solvent such as methylene chloride and chloroform from under cooling to under heating.
Step 13
Compound (XIII) can be synthesized by refluxing under heating compound (XII) in an acidic solvent such as formic acid and acetic acid. In this case, a dehydrating agent such as magnesium sulfate and sodium sulfate may be added.
Step 14
This step is for the synthesis of compound (XIII) from compound (XI) in a single step, and o und (XIII) can be synthesized from compound (XI) and carboxylic acid chloride such as acetyl chloride by the method described in Indian J. Chem., 20B: 322-323 (1981). When R2 is methyl, compound (XIII) can be synthesized by reacting compound (XI) and acetic anhydride while heating in acetic acid.
Step 15
Compound (I) can be synthesized by reacting compound (XIII) in the presence of a chlorosulfonylating agent such as chlorosulfonic acid in an organic solvent such as chloroform and methylene chloride, or without solvent, and subjecting the resulting product to amination, alkylamination or alkylation by a known method. The amination and alkylamination in Step 15 specifically comprise reacting in the presence of aqueous ammonia, alkylamine or a base such as sodium acetate and ammonium salt such as alkylamine hydrochloride in an organic solvent such as tetrahydrofuran, ether, toluene, benzene, methylene chloride and dioxane from under cooling to under heating. When alkylsulfonation is carried out, the method described in J. Org. Chem., 56: 4974-4976 (1991) can be used for the synthesis.
In the above description, alkylsulfonation or aminosulfonation in the final Step 15 has been exemplary discussed. It is possible to use compound (II) and compound (III) instead of the starting materials (IIxe2x80x2) and (IIIxe2x80x2) to give compound (IV), which is followed by Step 11 to Step 14 to give an oxazole compound (I). In this case, Step 15 is not necessary.
Compound (XIII) used in Step 15 can be also synthesized by the following route. 
wherein Rxe2x80x2, R1xe2x80x2, R2 and Z are as defined above.
Step 16
Compound (VIxe2x80x2) can be synthesized in the same manner as in Step 2 wherein compound (IVxe2x80x2) is reacted in the presence of lead tetraacetate in acetic acid solvent, or by heating compound (IVxe2x80x2) in the presence of a complex such as manganese acetate in lower akanecarboxylic acid such as acetic acid and propionic acid corresponding to R2COOH wherein R2 is as defined above, and benzoic acid and in a solvent such as benzene as necessary.
Step 17
Compound (XIII) can be synthesized in the same manner as in Step 3 wherein compound (Vxe2x80x3) is refluxed under heating in the presence of ammonium salt such as lower alkanecarboxylic acid ammonium (e.g., ammonium acetate and ammonium formate) and inorganic ammonium (e.g., ammonium carbonate) in an acidic solvent of lower alkanecarboxylic acid such as formic acid, acetic acid and propionic acid. In this reaction, when Rxe2x80x2 or R1xe2x80x2 is an aromatic heterocycle, isomers may be produced wherein the 4-position Rxe2x80x2 and the 5-position R1xe2x80x2 are reversed.
Compound (I) can be also synthesized by the method shown in the following Step 18 to Step 21. 
wherein X2 is halogen atom, and R, R1, Rxe2x80x2, R1xe2x80x2, R2 and Z are as defined above.
Step 18
Compound (XV) can be synthesized by reacting compound (XIV) with chlorbonate such as ethyl chlorocaronate in an inert solvent such as tetrahydrofuran, toluene and ethyl acetate in the presence of a base such as triethylamine, or by heating compound (XIV) in acetic anhydride.
Step 19
Compound (XVII) can be synthesized by reacting compound (XV) with compound (XVI) or an acid anhydride corresponding to compound (XVI) in an inert solvent such as tetrahydrofuran, acetonitrile, ethyl acetate and toluene in the presence of magnesium salt such as magnesium chloride and a base such as triethylamine, pyridine and potassium carbonate. Compound (XVII) can be also synthesized by the method described in Chem. Ber., 102: 883-898 (1969).
Step 20
Compound (XVIII) can be synthesized by treating compound (XVII) with an acid such as 1N-4N hydrochloric acid, oxalic solid and dilute sulfuric acid in an inert solvent such as tetrahydrofuran, dioxane, methylene chloride and toluene, or heating compound (XVII) in the presence of pyridine and acetic acid.
Step 21
Compound (I) is obtained by reacting compound (XVIII) with a chlorosulfonylating agent such as chlorosulfonic acid in an organic solvent such as chloroform and methylene chloride, or without solvent. Then, the obtained product is reacted with aqueous ammonia or alkylamine in an orgnic solvent such as tetrahydrofuran, ether, toluene, methylene chloride and dioxane, or reacted with ammonium salt such as alkylamine hydrochloride in the presence of a base such as sodium acetate, pyridine and sodium hydroxide.
Compound (I) can be also synthesized from compound (XVIII) by the following Step 22 and Step 23.
Step 22
Compound (XIII) can be synthesized by reacting compound (XVIII) with inorganic acid such as concentrated sulfuric acid and polyphosphoric acid in acetic anhydride, or without solvent, at room temperature to under heating.
Step 23
Compound (I) can be synthesized by reacting compound (XIII) in the same manner as in the aforementioned. Step 15.
In the above Step 22 and Step 23, alkylsulfonylation or aminosulfonylation in the final Step 23 has been exemplary discussed. It is possible to subject a compound having R and R1 instead of Rxe2x80x2 and R1xe2x80x2 to the reaction according to Step 18 to Step 20, followed by Step 22 to give an oxazole compound (I). In this case, Step 23 is not necessary.
The compound (I) thus obtained can be isolated and purified by a known method for separation and purification, such as concentration, concentration under reduced pressure, solvent extraction, crystal precipitation, recrystallization and chromatography.